Alcoholism is a chronic relapsing disorder characterized by periods of high alcohol intake (binges), acute withdrawal, protracted abstinence and relapse. Particularly important is the stage of protracted abstinence which can be defined as a state of heightened reactivity to aversive and appetitive stimuli long after acute withdrawal that conveys a vulnerability to relapse in individuals with a history of dependence. Animal models exist for all stages of the addiction cycle and have been useful in elucidating the neurobiological basis for vulnerability to alcoholism. The purpose of this proposal is to establish animal and human models of various stages of the addiction cycle with a focus on predicting efficacy of medications to treat the protracted abstinence stage of the alcoholic syndrome and protect against relapse. Preliminary studies have shown that rats can be trained to self-administer alcohol and, when made dependent, increase their consumption during acute withdrawal and long after acute withdrawal. Studies are proposed to further characterize and develop these animal models of the addiction cycle. Neuropharmacological agents known to alter reward dysregulation will be tested on these models (Specific Aim 1) to identify novel potential treatments for human laboratory testing (Specific Aim 2). In parallel, a human experimental model of various components of the addiction cycle will be developed and validated using cue reactivity and mood induction techniques in the lab and assessment of drinking, mood and sleep under natural conditions (Specific Aim 3). The optimal parameters of the human laboratory model will be used to evaluate potential treatments for various components of the addiction cycle (Specific Aim 4), drawing on the pharmacological agents identified in the animal models of Specific Aim 2. A focus on various components of the addiction cycle in alcoholism is critical for understanding vulnerability to relapse, and the results of the present proposed studies will provide novel treatments for such components including protracted abstinence and thus unique approaches to alcoholism treatment.